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Metastatic Breast CancerPhase 3NCT02051218

Prevention of Symptomatic Skeletal Events With Denosumab Administered Every 4 Weeks Versus Every 12 Weeks

A Phase 3 study testing Denosumab (reduced dosing) and Denosumab (standard dosing) in people with Metastatic Breast Cancer and Metastatic Prostate Cancer, run by Swiss Cancer Institute at 50 sites in 3 countries.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record

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Trial summary

The aim of the trial is to test the hypothesis that the benefit of denosumab is maintained if administered only every 12 weeks as compared to every 4 weeks. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Denosumab (reduced dosing) and Denosumab (standard dosing)
Could I receive a placebo?
No, everyone receives an active treatment
How many people
1,380 participants
Where
50 sitesin 3 countries
Study dates
16 Jul 2014to 20 Mar 2026
Phase
Phase 3

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patient has given written informed consent.
  • Histologically confirmed diagnosis of breast or prostate cancer before randomization.
  • Patient has metastatic breast cancer (stage IV, all subtypes allowed) or prostate cancer (stage IV) and bone metastases and is planned to receive or is receiving antineoplastic treatment.
  • Patients with prostate cancer must have evidence of disease progression on continuous androgen deprivation therapy (CRPC).
  • Patients must have ≥ 3 bone metastases (lytic or blastic or mixed). The lesions must be documented by radiological evaluation within 12 weeks before randomization (by X-Ray, CT scan, PET-CT, MRI scan or bone scintigraphy).
  • WHO performance status 0-2
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  • Age ≥ 18 years.
  • Corrected serum calcium ≥ 2 mmol/l and ≤ 3 mmol/l (medical treatments to obtain serum calcium levels in the normal range are allowed, as far as no denosumab is used. Maximally 1 dose of bisphosphonates in the case of hypercalcemia is allowed, if the bisphosphonate was applied at least 3 weeks before the first dose of denosumab).
  • Liver transaminases not more than 1.5 x ULN or not more than 3 x ULN with liver metastases. Serum total bilirubin ≤ 1.5 x ULN (≤ 2.0 x ULN in case of known Gilbert's disease)
  • Women are not breastfeeding. Women with child-bearing potential are using effective contraception, are not pregnant and agree not to become pregnant during participation in the trial and during the 12 months thereafter. A negative pregnancy test before inclusion (within 7 days) into the trial is required for all women with child-bearing potential.
  • Men agree not to father a child during participation in the trial and during 12 months thereafter.

Who cannot join

  • Definite contraindication for denosumab (e.g. hypocalcaemia [Albumin-corrected serum calcium < 2.0 mmol/l]).
  • History or current evidence of osteonecrosis of the jaw.
  • Non-healed mucosa in oral cavity (by surgery or as a side effect of any other treatment).
  • Jaw or dental conditions that require oral surgery or if surgery or invasive dental procedures are planned.
  • Prior use of denosumab for bone metastases (dose 120 mg every 4 weeks) or bisphosphonates to treat bone metastases. Patients treated with denosumab or bisphosphonates against osteopenia or osteoporosis are allowed to enter the trial if the last dose was more than 28 days before randomization.
  • Patients with known osteoporosis (T-score ≤ -2.5) at study entry (since fractures from osteoporosis are difficult to be discriminated from fractures through bone metastases).
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  • Radiotherapy or surgery to the bone within the last two weeks before randomization or planned within 6 weeks after randomization.
  • Presence or history of CNS metastases or leptomeningeal disease. A MRI evaluation within 12 weeks before randomization must be performed in case of suspicious symptoms.
  • Psychiatric disorder precluding understanding of information on trial related topics, giving informed consent, filling out QoL forms.
  • Concurrent treatment in a clinical trial with SSE or SRE as primary endpoint.
  • Known hypersensitivity to trial drug or hypersensitivity to any other component of the trial drug (e.g. fructose).
  • Any concomitant drugs contraindicated for use with the trial drugs according to the approved product information.
  • Any psychological, familial, sociological or geographical condition potentially hampering compliance with the trial protocol.

Trial locations and contacts

50 sites in 3 countries.

50 sites in 3 countries

Switzerland43 sites

  • Hirslanden Klinik Aarau

    Aarau, CH-5001

  • Kantonspital Aarau

    Aarau, CH-5001

  • Kantonsspital Baden

    Baden, CH-5404

  • Universitaetsspital Basel

    Basel, 4031

  • Brustzentrum Basel - Praxis für ambulante Tumortherapie

    Basel, 4052

  • St. Claraspital AG

    Basel, CH-4016

  • Istituto Oncologico della Svizzera Italiana - Ospedale Regionale Bellinzona e Valli

    Bellinzona, 6500

  • Klinik Engeried / Praxis Oncocare

    Bern, 3012

  • Inselspital, Bern

    Bern, CH-3010

  • Spitalzentrum Biel

    Biel, CH-2501

  • Spitalzentrum Oberwallis

    Brig, 3900

  • Centre du Sein de Genève, Clinique des Grangettes

    Chêne-Bougeries, 1224

  • Kantonsspital Graubünden

    Chur, 7000

  • Kantonsspital Frauenfeld - Brustzentrum

    Frauenfeld, 8501

  • Hopital Fribourgeois

    Fribourg, 1708

  • Hopitaux Universitaires de Geneve

    Geneva, 1211

  • Clinique De Genolier

    Genolier, 1272

  • Hôpital neuchâtelois

    La Chaux-de-Fonds, 2300

  • CCAC Lausanne

    Lausanne, 1004

  • CHUV

    Lausanne, 1011

  • Kantonsspital Liestal

    Liestal, CH-4410

  • Fondazione Oncologia / Oncologia ematologia

    Locarno, 6600

  • Luzerner Kantonsspital

    Lucerne, 6000

  • Hirslanden Klinik St. Anna Luzern

    Lucerne, 6006

  • Oncologia Varini & Calderoni & Christinat

    Lugano, 6900

  • Onkologie Zentrum Spital Männedorf

    Männedorf, 8708

  • Kantonsspital Muensterlingen

    Münsterlingen, 8596

  • Kantonsspital Olten

    Olten, 4600

  • Tumor and Brustzentrum Ostschweiz TBZO

    Sankt Gallen, 9016

  • Tumor and Brustzentrum Ostschweiz TBZO

    Sankt Gallen, CH-9006

  • Kantonsspital St. Gallen

    Sankt Gallen, CH-9007

  • Rundum Onkologie am Bahnhofpark

    Sargans, 7320

  • Spital Limmattal

    Schlieren, 8952

  • Hôpital du Valais Sion

    Sion, Sion, 1951

  • Bürgerspital Solothurn - Zentrum für Onkologie und Hämatologie

    Solothurn, 4500

  • Spital STS AG

    Thun, 3600

  • Kantonsspital Winterthur

    Winterthur, 8401

  • Brustzentrum-Zürich

    Zurich, Canton of Zurich, 8005

  • Klinik für Hämatologie und Onkologie Hirslanden Zürich AG

    Zurich, Canton of Zurich, 8032

  • Universitätsspital Zürich

    Zurich, Canton of Zurich, 8091

  • Stadtspital Zürich Triemli

    Zurich, Canton of Zurich, CH-8063

  • Onkologie Bellevue

    Zurich, 8001

  • Onkozentrum Klinik im Park

    Zurich, 8038

Other trials in Switzerland

Germany5 sites

  • Uniklinik Düsseldorf, Urologische Klinik

    Düsseldorf, 40225

  • Universitätsklinikum Düsseldorf, Frauenheilkunde/Geburtshilfe

    Düsseldorf, 40225

  • Universitätsmedizin Göttingen

    Göttingen, 37075

  • Universitätsklinikum Schleswig-Holstein

    Lübeck, 23538

  • Universitäts-Frauenklinik Ulm

    Ulm, 89075

Other trials in Germany

Austria2 sites

  • Landeskrankenhaus Feldkirch

    Feldkirch, 6800

  • Klinikum Wels-Grieskrichen GmbH

    Wels, 4600

Other trials in Austria

About this study

Official title: Prevention of Symptomatic Skeletal Events With Denosumab Administered Every 4 Weeks Versus Every 12 Weeks - A Non-Inferiority Phase III Trial

The aim of the trial is to test the hypothesis that the benefit of denosumab is maintained if administered only every 12 weeks as compared to every 4 weeks.

Read the detailed description

Denosumab, a monoclonal antibody against RANK-Ligand has been shown superior to zoledronic acid in delaying time to a first on-study skeletal related event (SRE) in patients with solid tumors, with no effects on disease progression or survival. Many SREs were silent compression fractures found only because of scheduled imaging. The approved dose of denosumab is 120 mg s.c. every 4 weeks (q4w). Although generally well tolerated, there is a time-dependent increase in osteonecrosis of the jaw in up to 8% of patients. Cases of fatal hypocalcaemia were observed during post marketing surveillance.

The optimal dose and schedule for denosumab is unknown. Denosumab is associated with considerable costs and may add toxicity; thus a study of de-escalation is warranted.

The aim of the trial is to test the hypothesis that the benefit of Denosumab is maintained if administered 120 mg q12w as compared to 120 mg q4w. The primary endpoint of this open-label randomized phase III non-inferiority trial is time to first on-trial symptomatic skeletal event (SSE: i.e. clinically significant pathological fracture, radiation therapy to bone, surgery to bone or spinal cord compression). With a non-inferiority margin of 1.2 for the hazard ratio, a power 80% and a type I error 5%, the total sample size is 1380. Secondary endpoints are safety, time to subsequent on-trial SSE, quality of life, health economic outcomes, and change in bone turnover markers. This study is open for international collaboration.

Being tested
Denosumab (reduced dosing), Denosumab (standard dosing)
Keywords
metastatic breast cancer, castration resistant metastatic prostate cancer, bone metastases, Denosumab, XGEVA, de-escalation
Medical subject headings
Breast Neoplasms, Prostatic Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Denosumab (reduced dosing)Drug

    Also called XGEVA®

    3x Denosumab 120mg (XGEVA®) sc. q4w followed by Denosumab 120mg (XGEVA®) sc. q12w

  • Denosumab (standard dosing)Drug

    Also called XGEVA®

    Denosumab 120mg (XGEVA®) sc. q4w

Study groups in NCT02051218
Study groupRoleWhat they receive
Arm A (standard arm)Active comparatorDenosumab 120mg (XGEVA®) sc. q4w
Receives: Drug: Denosumab (standard dosing)
Arm B (reduced arm)ExperimentalDenosumab 120mg (XGEVA®) sc. q4w [weeks 1, 5, 9] followed by Denosumab 120mg (XGEVA®) sc. q12w [weeks 13, 25, …]
Receives: Drug: Denosumab (reduced dosing)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Time to first on-trial symptomatic skeletal event (SSE; Clinically significant pathological fracture, radiation therapy to bone, surgery to bone or spinal cord compression).

    A SSE is defined as one of the following events: Clinically significant pathological fracture, radiation therapy to bone, surgery to bone, or spinal cord compression.

    Measured: at the latest 5 years after randomization.

Secondary outcomes (8)

  1. Toxicity (focus on hypocalcaemia and osteonecrosis of the jaw)

    Measured: at the latest 5 years after randomization.

  2. Time to first and subsequent on-trial SSE

    Measured: at the latest 5 years after randomization.

  3. Quality of Life measured by FACT-G and FACT-BP

    Measured: at the latest 5 years after randomization.

  4. Skeletal morbidity period rate (SMPR)

    Measured: at the latest 5 years after randomization.

  5. Skeletal morbidity rate (SMR)

    Measured: at the latest 5 years after randomization.

  6. Health economic analysis

    Measured: at the latest 5 years after randomization.

  7. Bone turnover markers

    Measured: at the latest 5 years after randomization.

  8. Overall Survival (OS)

    Measured: at the latest 5 years after randomization.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted31 Jan 2014 (estimated)
  2. Study start16 Jul 2014
  3. Primary completion20 Mar 2026
  4. Study completion20 Mar 2026

Why it stopped: Board decision as by March 2026, the number of patients undergoing treatment decreased to around 50, from the total 1,380 patients enrolled in the trial. And due to price changes in medication

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Supportive care
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
1,380 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02051218
Sponsor's protocol ID
SAKK 96/12
Other IDs
000000685, 2014-001189-87, 2014
Status last verified
Oct 2026
First submitted
29 Jan 2014
Last updated
23 Oct 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No

Publications

  • Adams A, Jakob T, Huth A, Monsef I, Ernst M, Kopp M, Caro-Valenzuela J, Wockel A, Skoetz N. Bone-modifying agents for reducing bone loss in women with early and locally advanced breast cancer: a network meta-analysis. Cochrane Database Syst Rev. 2024 Jul 9;7(7):CD013451. doi: 10.1002/14651858.CD013451.pub2.

    PubMed 38979716

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